Cyclic AMP-dependent and cyclic AMP-independent actions of a novel cardiotonic agent, OPC-8212

Abstract

Possible cAMP-dependent and cAMP-independent mechanisms of action for the cardiac effects of OPC-8212, a novel piperazinyl-quinolinone derivative, were evaluated. OPC-8212 was tested for in vitro potency as an inhibitor of soluble bovine cardiac phosphodiesterases using a rapid isolation and assay method involving monoclonal antibodies that distinguish among isozymes. The drug was selective for a low-Km, cGMP-inhibited phosphodiesterase (CGI-PDE) with an IC50 (half-maximal inhibition concentration) of 7.4 mumol/l when measured at a substrate level of 0.35 mumol/l cAMP. Under the conditions used, sulfolane, the solvent for OPC-8212, did not affect CGI-PDE activity. In electrophysiological measurements, OPC-8212 prolonged the action potential duration in canine Purkinje strand preparations up to 148% (APD90) at 10 mumol/l. Concomitantly, OPC-8212 produced a 100% increase in developed force. Both prolongation of the action potential duration and the positive inotropic effect were readily reversed after exposure to tetrodotoxin, 3 mumol/l. Using Na-selective microelectrodes, intracellular Na+ ion activity increased 225% upon exposure to 10 mumol/l OPC-8212. OPC-8212 represents a novel type of positive inotropic agent, possessing both cAMP-dependent (selective PDE isozyme inhibition) and cAMP-independent (activation of intracellular Na+) mechanism of action.